The concepts of genetic therapies for the treatment of genetic defects or providing intracellular immunity to viral infection have been entertained for a number of years (see Baltimore, 1988 (1); Szybalski, 1992 (2)). Gene therapy has recently received more attention for its potential utility in the treatment of HIV infection (Sarver and Rossi, 1993 (3)). A number of different inhibitory strategies have been tested for conferring resistance to HIV-1, including those encoding antisense RNA, ribozymes (Rz), TAR or RRE decoys, trans-dominant mutant HIV-1 genes and conditionally lethal toxins (reviewed in Sarver and Rossi, 1993 (3)).
RNA-based strategies, such as antisense or Rz, have the dual advantages of being sequence-specific, theoretically eliminating unwanted toxicities, as well as not producing potentially immunogenic proteins. A single Rz molecule is capable of irreversibly inactivating multiple target RNA molecules by sequential cycles of binding, cleavage and release, but even in the absence of multiple substrate turnover, Rz functionally inactivate target RNAs via cleavage (Zaug and Cech, 1986 (4); Uhlenbeck, 1987 (5); Castanotto, et al., 1992 (6)).
Retroviral vectors currently comprise a relatively efficient system for gene transduction of mammalian cells, including human lymphocytes and hematopoietic cells (Mulligan, 1993 (7); Williams, 1990 (8)). Retroviral vectors and packaging cell lines have been developed which have extremely low probabilities of producing replication-competent retroviruses and are increasingly used for clinical gene marking and gene therapy trials (Miller and Rosman, 1989 (9); Miller, 1990 (10); Anserson, et al., 1993 (11).